ABCA3 as a Possible Cause of Drug Resistance in Childhood Acute Myeloid Leukemia

• Published in: Clinical cancer research 2006-07, Vol.12 (14), p.4357-4363
• Main Authors: STEINBACH, Daniel, GILLET, Jean-Pierre, SAUERBREY, Axel, GRUHN, Bernd, DAWCZYNSKI, Kristin, BERTHOLET, Vincent, DE LONGUEVILLE, Francoise, ZINTL, Felix, REMADE, Jose, EFFERTH, Thomas
• Format: Article
• Language: English
• Subjects: ABC transporter; acute myeloid leukemia; Adolescent; Adult; Antineoplastic agents; ATP-Binding Cassette Transporters - metabolism; ATP-Binding Cassette Transporters - physiology; Biological and medical sciences; Bone Marrow Cells - metabolism; Child; Child, Preschool; Cluster Analysis; Drug Resistance, Multiple; Drug Resistance, Neoplasm; expression profiling; Female; Gene Expression Regulation, Neoplastic; Hematologic and hematopoietic diseases; Humans; Jurkat Cells; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; multi drug resistance; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; RNA, Small Interfering - metabolism
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2587

Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. Multidrug resistance can be caused by ATP-binding cassette (ABC) transporters that function as drug efflux pumps. The majority of these proteins have not yet been examined in malignant diseases. Experimental Design: A newly developed microarray for the simultaneous quantification of 38 ABC transporter genes and Taqman real-time PCR was used to analyze the expression of ABC transporters in pediatric AML and healthy bone marrow. Small interfering RNA was used to verify the role of ABCA3 in drug resistance. Results: Using the microarray, we identified four new ABC transporters, which were overexpressed in many AML samples compared with healthy bone marrow: ABCA2, ABCA3, ABCB2 , and ABCC10 . The overexpression of these four genes was verified by real-time PCR in 42 samples from children with AML and 18 samples of healthy bone marrow. The median expression of ABCA3 was three times higher in 21 patients who had failed to achieve remission after the first course of chemotherapy than in a well-matched group of 21 patients who had achieved remission at this stage ( P = 0.023). Incubation of cell lines with a number of different cytostatic drugs induced an up-regulation of ABCA3. Down-regulation of ABCA3 by small interfering RNA sensitized cells to doxorubicin. Conclusion: Our results show that ABCA2, ABCA3, ABCB2, and ABCC10 are overexpressed in childhood AML compared with healthy bone marrow. ABCA3 is the most likely transporter to cause drug resistance.